Age-related Macular Degeneration (AMD) is the most common cause of permanent vision loss in industrialized countries. While some risk factors are known, the ability to identify those subjects most at risk is still limited. We have shown that using advanced imaging techniques middle-aged individuals have varying amounts of early changes in the photoreceptor/Retinal Pigment Epithelium/Bruch's membrane complex. The long term goal is to detect the earliest changes related to inflammatory processes, so that targeted treatments can be devised to prolong vision and prescribed to only appropriate subjects, thereby reducing side effects for those who do not have early changes. The early damage to the human fundus that is predicted by inflammatory models will be probed with noninvasive laboratory methods to target separately Bruch's membrane/Retinal Pigment Epithelium, cone photoreceptor outer segments, and cone and rod cell bodies in the Outer Nuclear Layer. This project directly addresses Program Goals of the National Eye Institute, particularly With regard to macular degeneration, understand the molecular and biochemical bases for its different forms, improve early diagnosis. In Aim 1, we will investigate the earliest possible changes to the photoreceptors using adaptive optics imaging and high resolution OCT. In Aim 2, we will quantify disruption to the Retinal Pigment Epithelium using polarized light imaging. In Aim 3, we will develop and use novel fluorescence techniques to map the spatial variations in fluorophores of lipofuscin. In Aim 4, we will further develop polarization sensitive OCT to probe inflammatory signs within and beneath the retinal pigment epithelium, as these is predicted to increase not only the thickness but also the phase retardation. In Aim 5, we will use quantitative data and novel techniques to test models that hypothesize that inflammatory changes are a unifying concept predicting all of the age- related increase in structural markers measured in Aims 1-4. Further, we will develop new techniques that are broadly applicable for microscopy and biomedical imaging. PUBLIC HEALTH RELEVANCE: Age-related Macular Degeneration is the leading cause of irreversible vision loss in industrialized countries. Using state of the art imaging and fluorescence measurements, we will characterize early changes to the photoreceptors, retinal pigment epithelium, and Bruch's membrane in the eyes of healthy adults. We will test whether the damage can be modeled as the early occurrence of an inflammatory response that differs among individuals and who could benefit from personalized treatment.